Abstract: Objective This experiment aimed to explore the potential mechanism by which Janagliflozin (JAGN) ameliorates liver steatosis in mice with high-fat diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) by inhibiting dipeptidyl peptidase-4(DPP4)/NOX1 mediated oxidative stress. Method 30 C57BL/6 mice were randomly divided into control, model and intervention group, with 10 mice in each. The model was established by high fat diet feeding, and intervention was completed by JAGN gavage. Hepatic homogenate malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) level was routinely detected. ROS level was determined by immunofluorescence, cell apoptosis was finished by TUNEL staining, DPP4 and nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) mRNA an their protein expression were assayed by real time fluorescence quantitative PCR and Western blot. Results Liver steatosis was found in model mice, suggesting the model was successfully established, and in JAGN-intervened group, liver steatosis was obviously ameliorated; hepatic homogenate MDA level was (4.5±0.6)μmol/L, much higher than [(2.7±0.4)μmol/L, P<0.05] in the control, while it turned to (3.1±0.9)μmol/L in the intervention group, much lower than in the model (P<0.05), GSH and SOD levels in the model were (6.5±1.1)mg/g and (0.1±0.1)U/mg, both much lower than [(8.5±1.4)mg/g and (0.5±0.1)U/mg, respectively, P<0.05] in the control, while they turned to (9.7±2.1)mg/g and (0.3±0.1)U/mg in the JAGN-intervened group, much higher than in the model (P<0.05); hepatic ROS level in the model was much higher than in the control (P<0.05), while it decreased greatly in the intervention group (P<0.05); apoptosis was obvious in the model, and it alleviated in the intervention group; hepatic DPP4 activity in the model was higher than in the control (P<0.05), while it decreased greatly in the intervention group(P<0.05); hepatic DPP4 and NOX1 mRNA level and protein expression in the model were higher or stronger than in the control(P<0.05), while they became lower or weaker in the JAGN-intervened group (P<0.05). Conclusion Janagliflozin could alleviate liver steatosis in mice with MAFLD, which might be related to the inhibition of DPP4/NOX1 mediated oxidative stress.

Key words: Metabolic dysfunction-associated fatty liver disease, Liver steatosis, Sodium glucose cotransporter 2 inhibitor, Oxidative stress, Mice